Substituted uracil derivatives as potent inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1)

Henning Steinhagen; Michael Gerisch; Joachim Mittendorf; Karl-Heinz Schlemmer; Barbara Albrecht

doi:10.1016/s0960-894x(02)00602-9

Substituted uracil derivatives as potent inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1)

Bioorg Med Chem Lett. 2002 Nov 4;12(21):3187-90. doi: 10.1016/s0960-894x(02)00602-9.

Authors

Henning Steinhagen¹, Michael Gerisch, Joachim Mittendorf, Karl-Heinz Schlemmer, Barbara Albrecht

Affiliation

¹ Institute of Medicinal Chemistry, Pharma Research Centre, Bayer AG, D-42096, Wuppertal, FRG . henning.steinhagen@aventis.com

PMID: 12372530
DOI: 10.1016/s0960-894x(02)00602-9

Abstract

A new class of PARP-1 inhibitors, namely substituted fused uracil derivatives were synthesised. Starting from a derivative with an IC(50)=2microM the chemical optimisation program led to compounds with more than a 100-fold increase in potency (IC(50)<20nM). Additionally, physicochemical and pharmacokinetic properties were evaluated. It could be shown that compounds bearing a piperazine or phenyl substituted betaAla-Gly side chain exhibited the best overall profile.

MeSH terms

Animals
Area Under Curve
Chemical Phenomena
Chemistry, Physical
Chromatography, High Pressure Liquid
Drug Design
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacokinetics
Enzyme Inhibitors / pharmacology*
Humans
Indicators and Reagents
Magnetic Resonance Spectroscopy
Male
Poly(ADP-ribose) Polymerase Inhibitors*
Rats
Rats, Wistar
Recombinant Proteins / antagonists & inhibitors
Structure-Activity Relationship
Uracil / analogs & derivatives*
Uracil / chemical synthesis
Uracil / pharmacology*

Substances

Enzyme Inhibitors
Indicators and Reagents
Poly(ADP-ribose) Polymerase Inhibitors
Recombinant Proteins
Uracil